Optical isomers of an iloperidone metabolite

ABSTRACT

The invention provides compounds of formulae (I) and (II), their preparation and their use as pharmaceuticals.

The present invention relates to novel isomers of a metabolite ofIloperidone, their preparation, their use as pharmaceuticals andpharmaceutical compositions containing them.

More particularly, the invention relates to optical isomers of themetabolite P-88-8991 of Iloperidone.

Iloperidone is an atypical antipsychotic developed for the treatment ofschizophrenia, having functional affinity for noradrenergic,dopaminergic and serotoninergic receptors. See for example Richelson E.and Souder T., Life Sciences, 68:29-39 (2000).

P-88-8991 is a major circulating metabolite of Iloperidone in humanplasma, having the formula A

See for example Mutlib AE et al., Drug Metab. Dispos; 23(9):951-964(1995). P-88-8991 has been shown to have plasma levels in human about1.5 fold higher than the parent drug. It is roughly as active asIloperidone.

P-88-8991 consists of a mixture of two enantiomers which have never beendisclosed in the literature. It has now surprisingly been found thathumans produce only one enantiomer stereospecifically followingadministration of Iloperidone.

In the first aspect, the invention provides the enantiomers(R)-P-88-8991 and (S)-P-88-8991 of formulae I and II

in free base or acid addition salt form.

In a further aspect, the invention provides a process for the productionof the compounds of formulae I and II, comprising the reduction ofIloperidone of formula III

with an optically active boran complex of formula IV

The compound(S)-1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanolof formula I is obtained using the boran complex of (3aR,7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole offormula IVa

whereas the compound(R)-1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]propoxy}-3-methoxy-phenyl)-ethanolof formula II is obtained using the boran complex of(3aS,7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaboroleof formula IVb

The reactions can be effected according to conventional methods, e.g. asdescribed in the Examples.

Working up the reaction mixtures and purification of the compounds thusobtained may be carried out in accordance to known procedures.

Acid addition salts may be produced from the free bases in known manner,and vice-versa. Suitable acid addition salts for use in accordance withthe present invention include for example the hydrochloride.

The boran complexes used as starting materials can be produced from thecorresponding compounds of formula Va and Vb

according to known procedures, e.g. as described in the Examples.

The starting materials of formulae Va and Vb are known.

The compounds of formulae I and II and their pharmaceutically acceptableacid addition salts, hereinafter referred to as agents of the invention,exhibit valuable pharmacological properties when tested in vitro and inanimals, and are therefore useful as pharmaceuticals.

In particular the agents of the invention display high affinity foradrenergic α₁ and α_(2c) receptors (pK_(I) 8.9 and 7.8 respectively, forthe compound of formula I, and 9.2 and 7.7 respectively, for thecompound of formula II), high affinity for 5 HT_(2A) and 5 HT₆ receptors(pK_(I) 8.9 and 8.1 respectively, for the compound of formula I, and 8.9and 7.8 respectively, for the compound of formula II) and moderateaffinity for the D₂ family (pK_(I) 7.4 to 7.6 for the compound offormula I and 7.4 to 7.8 for the compound of formula II).

Receptor affinity is determined with standard radioligand bindingtechniques, using human recombinant receptors and native rat brainreceptors. Blockade of dopamine D₂ and noradrenergic α_(2c) receptors istested in cell-lines using luciferase reporter gene assays based on2^(nd) messenger responses.

In vivo, the agents of the invention exhibit antipsychotic activity, asassessed in standard tests such as the amphetamine-induced hypermotilityand the phencyclidine-induced hyperlocomotion tests.

The amphetamine-induced hypermotility test is performed according to themethod described by Arnt J in Eur. J. Pharmacol. 283, 55-62 (1995). Inthis test, the agents of the invention significantly inhibit theamphetamine-induced locomotion of the animals at doses of about 0.01 toabout 10 mg/kg s.c.

The phencyclidine-induced hyperlocomotion test is performed according toa rat adaptation of the method described by Gleason SD and Shannon HE inPsychopharmacol. 129, 79-84 (1997). In this test, the agents of theinvention significantly block the phencyclidine-induced hyperlocomotionof the rats at doses of about 0.01 to about 10 mg/kg s.c.

The agents of the invention are therefore useful for the treatment ofpsychotic disorders such as schizophrenia and bipolar disorders.

For the above-mentioned indications, the appropriate dosage will ofcourse vary depending upon, for example, the compound employed, thehost, the mode of administration and the nature and severity of thecondition being treated. However, in general, satisfactory results inanimals are indicated to be obtained at a daily dosage of from about 0.1to about 500, preferably from about 0.5 to about 100 mg/kg animal bodyweight. In larger mammals, for example humans, an indicated daily dosageis in the range from about 1 to about 500, preferably from about 1 toabout 300 mg of an agent of the invention, conveniently administered,for example, in divided doses up to four times a day or in sustainedrelease form.

The agent of the invention may be administered by any conventionalroute, in particular enterally, preferably orally, for example in theform of tablets or capsules, or parenterally, for example in the form ofinjectable solutions or suspensions.

The agents of the invention may alternatively be administered e.g.topically in the form of a cream, gel or the like, or by inhalation,e.g. in dry powder form.

Examples for compositions comprising an agent of the invention include,e.g. a solid dispersion, an aqueous solution, e.g. containing asolubilising agent, a microemulsion and a suspension of an agent of theinvention. The composition may be buffered to a pH in the range of e.g.from 3.5 to 9.5, by a suitable buffer.

The agents of the invention can be administered either alone or incombination with other pharmaceutical agents effective in the treatmentof psychotic disorders such as schizophrenia or bipolar disorders. Thepresent invention thus provides a combination comprising atherapeutically effective amount of an agent of the invention and asecond drug substance, for simultaneous or sequential administration.

In accordance with the foregoing, the present invention also provides anagent of the invention, for use as a pharmaceutical, e.g. for thetreatment of psychotic disorders.

The present invention furthermore provides a pharmaceutical compositioncomprising an agent of the invention in association with at least onepharmaceutical carrier or diluent. Such compositions may be manufacturedin conventional manner. Unit dosage forms contain, for example, fromabout 0.25 to about 150, preferably from 0.25 to about 25 mg of acompound according to the invention.

Moreover the present invention provides the use of an agent of theinvention, for the manufacture of a medicament for the treatment ofpsychotic disorders.

In still a further aspect the present invention provides a method forthe treatment of psychotic disorders, in a subject in need of suchtreatment, which comprises administering to such subject atherapeutically effective amount of an agent of the invention.

The following examples illustrate the invention.

EXAMPLE 1(S)-1-(4-{3-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanol

56.36 g of boran complex of (3aR,7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole (1equivalent) is dissolved under nitrogen in methylenchloride, and thesolution is cooled to 0° C. A 1M solution of1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone(iloperidone; 1 equivalent) in methylenchloride is added via a droppingfunnel over 90 minutes while the internal temperature is maintained at0° C.±2° C. After the addition is complete, the mixture is stirred at 0°C. for 20 hours. The reaction mixture is then poured into precooledmethanol (0-5° C.) during 1 hour. The solution is warmed to roomtemperature and stirred until the H₂ evolution ceases. The solution isconcentrated by distillation and the residue dried in vacuum, treatedwith methanol and stirred for about 1 hour at 50° C. and an additionalhour at 0° C. The product is isolated by filtration and dried underreduced pressure for 3 hours at 50° C. The title compound is obtained(white crystals).

[α]_(D) ²⁰−19.3° (c=1 in chloroform)

Mp: 138.2-138.8° C.

The boran complex used as starting material can be obtained as follows:

200 ml of a solution of (3aR,7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole(1M in toluene) is stirred at room temperature under nitrogen. 1.2equivalent borane-dimethylsulfide complex is added with a syringe. Thesolution is stirred for 2 further hours at room temperature. The boranecomplex is then crystallised by addition of 4 vol dry hexane and coolingto −12° C. for 1.5 hour. The product is isolated by filtration in asintered glass funnel and dried in vacuum at 40° C. The boran complex isobtained/white crystals).

EXAMPLE 2(R)-1-(4-{3-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenlyl)-ethanol

This compound is produced in analogy to Example 1, using boran complexof (3aS,7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole.

[α]_(D) ²⁰=+18.4° (c=1 in chloroform)

Mp: 137.9-138.3° C.

1.(R)-1-(4-{3-[4-(6-Fluoro-benzo[d]isoxazol-3-yl}-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanolof formula I

in free base or acid addition salt form. 2.(S)-1-(4-{3-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanolof formula II

in free base or acid addition salt form.
 3. A process for the productionof the compound of formula I according to claim 1, and its salts,comprising the reduction of Iloperidone of formula III

with an optically active boran complex of formula IV

and recovering the resulting compound in free base or acid addition saltform.
 4. A compound of claim 1 in free base or pharmaceuticallyacceptable acid addition salt form, for use as a pharmaceutical.
 5. Acompound of claim 1 in free base or pharmaceutically acceptable acidaddition salt form, for use in the treatment of psychotic disorders. 6.A pharmaceutical composition comprising a compound of claim 1 in freebase or pharmaceutically acceptable acid addition salt form, inassociation with a pharmaceutical carrier or diluent.
 7. The use of acompound of claim 1 in free base or pharmaceutically acceptable acidaddition salt form, as a pharmaceutical for the treatment of psychoticdisorders.
 8. The use of a compound of claim 1 free base orpharmaceutically acceptable acid addition salt form, for the manufactureof a medicament for the treatment of psychotic disorders.
 9. A methodfor the treatment of psychotic disorders in a subject in need of suchtreatment, which comprises administering to such subject atherapeutically effective amount of a compound of claim 1 in free baseor pharmaceutically acceptable acid addition salt form.
 10. Acombination comprising a therapeutically effective amount of a compoundof claim 1 in free base or pharmaceutically acceptable acid additionsalt form, and a second drug substance, for simultaneous or sequentialadministration.
 11. A process for the production of the compound offormula II according to claim 2, and its salts, comprising the reductionof Iloperidone of formula III

with an optically active boran complex of formula IV

and recovering the resulting compound in free base or acid addition saltform.
 12. A compound of claim 2 in free base or pharmaceuticallyacceptable acid addition salt form, for use as a pharmaceutical.
 13. Acompound of claim 2 in free base or pharmaceutically acceptable acidaddition salt form, for use in the treatment of psychotic disorders. 14.A pharmaceutical composition comprising a compound of claim 2 in freebase or pharmaceutically acceptable acid addition salt form, inassociation with a pharmaceutical carrier or diluent.
 15. The use of acompound of claim 2 in free base or pharmaceutically acceptable acidaddition salt form, as a pharmaceutical for the treatment of psychoticdisorders.
 16. The use of a compound of claim 2 in free base orpharmaceutically acceptable acid addition salt form, for the manufactureof a medicament for the treatment of psychotic disorders.
 17. A methodfor the treatment of psychotic disorders in a subject in need of suchtreatment, which comprises administering to such subject atherapeutically effective amount of a compound of claim 2 in free baseor pharmaceutically acceptable acid addition salt form.
 18. Acombination comprising a therapeutically effective amount of a compoundof claim 2 in free base or pharmaceutically acceptable acid additionsalt form, and a second drug substance, for simultaneous or sequentialadministration.